PROJECT SUMMARY/ABSTRACT Extensive progress was made in the previous funding period of the Rush Memory and Aging Project (MAP). We 1) elucidated the neuropathologic basis of cognitive decline due to Alzheimer?s disease and related disorders (ADRD), 2) discovered genomic, experiential, psychological, and medical risk factors for ADRD clinical and pathologic traits including numerous risk factors for Alzheimer?s dementia with little to no relationship with ADRD brain pathologies, and 3) identified numerous potential novel therapeutic targets for cognitive decline, especially targets for cognitive decline not explained by common brain pathologies i.e., resilience. Here, the average person has average resilience and individuals can be more or less resilient. Resilience is a high value therapeutic target because if druggable it would offset the effects of any combination of brain pathologies. In this funding cycle, we propose to continue to follow MAP participants and conduct autopsies, and in this cycle, to obtain skin biopsies at autopsy to support a powerful new drug discovery program that integrates existing brain omics data with a new human cellular model of disease, i.e., skin derived fibroblast cultures induced into neuronal lines from persons with more or less resilience. We propose to: 1) define a robust and specific molecular signature of resilience in the human brain; 2) identify gene targets of resilience and establish human low-resilience cell models derived from MAP participants of known resilience; and 3) conduct drug discovery screens in the low-resilience models to identify compounds that increase resilience. These aims are supported by compelling preliminary work. An Exploratory Aim will continue to identify risk factors for ADRD clinical and pathologic traits leveraging the rich resource generated from the exposure data, repeated measures, and neuropathologic traits . All aims will examine sex as a biologic variable. A Secondary Aim will continue to share the unique and valuable resources generated by MAP including the to-be-generated fibroblast cell lines with the scientific community. Harnessing mechanisms of resilience to ADRD can slow down or prevent cognitive decline regardless of the presence and complexity of common brain pathologies. Therefore, the genes and compounds identified from our study will provide new therapeutic remedies to boost brain reserve in combating ADRD-related dementia. We believe that the proposed continuation will have a high and sustained impact on the field of aging and dementia research.